AIDS is a destructive disease that has considerable social and financial implications for today's society. There are currently no cures or vaccines that effectively combat the debilitation of immune function induced by viral infection. Recent studies by several laboratories worldwide have demonstrated that AIDS infection promotes apoptosis (programmed cell death) in I HIV infected lymphocytes. The apoptotic process is likely to be the major cause of immune system compromise. Our laboratory is addressing three areas of research directly related to AIDS virus induced apoptosis in the immune system. 1) Molecular Mechanisms of Cyclophilin - Recent studies from our collaborators at NCI have shown that the AIDS virus GP120 cell surface protein selectively binds with affinity to the A 18KD cyclophlin molecule. We have shown that cyclophilin, in addition to acting as a companion protein, has catalytic activity that degrades DNA (nuclease). Thus, it is possible that cyclophilins delivered to lymphocytes by the HIV GP120 is an initiation of this process. We are currently characterizing the nuclease activity of cyclophilin and testing the hypothesis that delivery of cyclophilin to cells stimulates apoptosis. 2) Inhibitors of Apoptosis - Unlike AIDS, many viruses inhibit cellular apoptosis through expression of proteins that mimic the function of endogenous inhibitors of apoptosis. Evidence from our laboratory indicate that apoptosis is a recessive phenotype, kept in check by inhibitors. One goal of our work is to identify, clone, and study the regulation of cellular apoptosis inhibitors. 3) The Fate of Viral Nucleic Acid During Apoptosis - Although it is well recognized that the AIDS virus induces apoptosis in infected lymphocytes, it is unclear if viral nucleic acids is destroyed during apoptosis. We are now conducting experiments to evaluate this question.